This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Hereditary sensory and autonomic neuropathy type I (HSAN1) is caused by missense mutations in the SPTLC1 gene encoding a subunit of the enzyme serine palmitoyltransferase (SPT). We recently identified two novel deoxysphingoid bases (DSB), deoxysphinganine (DoxSA) and deoxymethylsphinganine (DoxMeSA), that accumulate in plasma of HSAN1 patients as well as of mice bearing a transgene expressing mutant SPTLC1. It appears that the mutant enzyme has a dramatically reduced reactivity with its normal preferred substrate serine and a promiscuously increased reactivity with alanine and glycine. In that these two amino acids, in contrast to serine lack hydroxyl groups, there is a shift in the mutant animals to formation of DSB that cannot be phosphorylated at the amino OH group. These observations suggest the hypothesis that a key to the pathophysiology of HSAN1 is the altered substrate selectivity of the enzyme with the corollary hypothesis that this could be overcome by mass action, that is, by flooding the enzyme environment in both mice and humans with L-serine, greatly in excess of alanine and glycine. In support of this hypothesis, in mutant mice on a 10% serine enriched diet DoxSA levels were reduced by 5-fold within 2 to 4 days. Once on the diet, these mice were dramatically protected from neurodegeneration on both measures of sensory (mechanical sensitivity) and motor performance (rotorod). In a pilot study of 14 human HSAN1 patients, we observed similar dramatic effects of L-serine supplementation. It is currently nuclear whether DoxSA and DoxMeSA are neurotoxic or other metabolites are involved. We have therefore undertaken the measurement of deoxydihydroceramides in 15 controls and 14 HSAN1 patients (on a off L-serine treatment) to assess whether this metabolic product of DoxSA may be the culprit of pathology seen in our mice.